Acromegaly, a rare disease that originates in a GH secreting pituitary tumor, is characterized by excess circulating GH and IGF-I and the multi-system morbidity and increased mortality they produce. Cardiovascular disease, a leading cause of death in acromegaly, may be related to the high prevalence of metabolic abnormalities, in particular insulin resistance. Our work suggests, however, that the paradigm linking metabolic abnormalities to CV disease in the general population does not apply in acromegaly. This project, utilizing our ongoing and unique prospective study of 300 patients with acromegaly, proposes, alternatively, a novel acromegaly-specific lipodystrophy that may underlie and perpetuate these abnormalities. The lipodystrophy, we hypothesize, produces a unique pattern of adipose tissue (AT) redistribution, a reduced visceral adipose tissue (VAT) mass, yet increased intra-myocellular lipid (IMCL) and inter-muscular adipose tissue (IMAT) mass that may be causative of insulin resistance and reduced intra-hepatic lipid (IHL) despite insulin resistance. Acromegaly therapies, pituitary tumor removal by surgery and medical therapy with somatostatin analogs (SSA) or GH receptor blockade, may not uniformly reverse this lipodystropy. We hypothesize, as our data suggest, that IHL increases with all therapies, VAT increases more after surgery and IMCL increases with SSA therapy. Aim 1 tests these hypotheses in an expanded acromegaly cohort in comparison to specially matched non-acromegaly groups and utilizing state of the art body composition testing. Aim 2 investigates mechanisms for therapy-specific body composition changes. Our recent data show that surgery leads to a clinically relevant gain in central adiposity that may relate to the postoperative rise n serum ghrelin. By contrast, the lowering of serum ghrelin on SSAs, we hypothesize, may contribute to less gain in central adiposity on this therapy. We will also test the hypothesis that disordered pancreatic and gut hormone secretion on SSA therapy predispose to IMCL accumulation, which may increase later risk of DM. Aim 3 investigates the lipodystrophy directly in AT, testing the hypothesis generated by our preliminary data that acromegaly produces a novel dissociation of inflammatory and immune cell phenotypes in AT that reverses when acromegaly is treated. Aim 4 will analyze 10-year morbidity and mortality outcomes in our well-characterized prospective cohort in relation to modern GH and IGF-1 measurements. This project will provide important guidelines for acromegaly therapy. Understanding the lipodystrophy, its consequences and reversal, is crucial to optimally treating patients, correcting their metabolic abnormalities and excess CV risk. This proposal is strengthened by its continuation of our ongoing prospective acromegaly cohort study, the only such study funded by the NIH, and our strong collaborative team. Acromegaly provides a model through which we can improve our knowledge about the effects of GH and IGF-I on adipose tissue inflammation, body composition, hepatic and muscle lipid accumulation and CV risk in other clinical settings as well as in acromegaly.